Ingemar Ingemarsson Memorial Symposium on preterm delivery at the <scp>XXI FIGO</scp> World Congress

Worldwide, preterm birth (PTB), particularly at early gestations, is the major cause of death and disability in neonates. In the EPICure Study (UK and Ireland 1995), approximately 65% of babies born between 22 and 26 completed weeks of gestation died on the labor ward or in the neonatal intensive care unit. At a follow up around 30 months age, approximately half of the surviving babies were disabled and in 50% of these the disability was severe such that only 12–13% were still alive and healthy. In the UK, the cost of hospital readmissions in the first 5 and 10 years of life is 20 times greater for babies born before 28 completed weeks of gestation compared with those born after 37 completed weeks. In 2007, the Institute of Medicine in the USA calculated that the annual cost associated with PTB was $26.2 billion, comprising medical costs for the baby ($16.9 billion), labor and delivery costs for the mother ($1.9 billion), early intervention programs for children with disabilities and developmental delays from birth to age 3 years ($611 million), special education services ($1.1 billion) and lost work and pay for the parents of these preterm babies ($5.7 billion). It has also been demonstrated that between 23 and 26 completed weeks of gestation, each day of prolongation of pregnancy increases the survival rate by 3%. The psychosocial costs of PTB are immeasurable. While the late Professor Ingemar Ingemarsson's contribution to Obstetrics was recognized in a memorial tribute in AOGS last year 1, the Nordic Federation of Societies of Obstetrics and Gynecology (NFOG) thought it appropriate to celebrate his work at an International Forum and with the encouragement and support of Professor Arulkumaran, a long-term friend and collegue of Ingemar, a symposium at the FIGO World Congress of Gynecology and Obstetrics 2015 in Vancouver, Canada, was arranged. Any number of subjects could have been chosen, but the organizers felt that PTB encompassed much of the scholarly activity that Ingemar undertook throughout his career, including fetal monitoring, tocolytics and mode of delivery. Five lectures were presented to reflect some of the contribution made by Professor Ingemarsson and his co-workers to the understanding and management of spontaneous preterm labor and PTB: (i) evolutionary aspects of human parturition (Bo Jacobsson); (ii) the extremely preterm infant (Karel Maršál); (iii) pharmacologic tocolysis (Ronnie Lamont); (iv) maternal obesity and PTB (Christina Anne Vinter); and (v) mode of delivery of the preterm infant (Jan Stener Jørgensen). The Symposium was chaired by Sven Montan and Knut Hordnes and we present a summary of these lectures. Improvements in neonatal care beyond those provided by improvements in obstetric care have resulted in increased survival for very early PTB neonates 2, 3. This is partly because our understanding of the parturition process is incomplete. To reduce the rate of PTB, we need to understand better those factors that provoke spontaneous preterm and post-term labor. Improved understanding of the genetics of parturition might help to develop better prevention strategies for PTB and also better methods for induction of labor. The evidence for a genetic influence on the timing of birth is derived from both family studies and ethnic/racial differences in the prevalence of PTB and is thought to account for about 11–35% of all PTBs. Women have an increased risk of PTB if they themselves were born preterm or if they had a previous PTB. There is also evidence that genetic factors through the maternal lineage are important, such that if a woman has a sister with a previous PTB she will also have an increased risk of PTB, but not so if her brother had an infant born preterm 4. In contrast, this does not apply to birthweight, birth length and head circumference, where paternal genes appear to have a greater influence 5. Several studies with multiple candidate gene designs have been performed with limited success to date 6, 7. In addition, complete genomewide associations studies have been carried out without success. From others traits that have been studied by genomewide associations studies, it appears that the breakthrough may only come when more than 10 000–100 000 individuals have been genotyped, together with high-quality phenotypic information. Several meta-analyses are under way which might contribute to the quality of studies and the number of individuals included. Another important aspect is the maturity of the baby at birth. Human offspring are born much more dependent on their mother than other primates. The classical hypothesis regarding this phenomenon is known as the obstetric dilemma, which means that the narrowing of the human pelvis due to the human bipedalism conflicts with the increased head size of the baby. The human evolutionary solution to this is to shorten the duration of the pregnancy with the consequence of a more dependent baby. An alternative suggestion is that maternal metabolism limits the maximum time in utero and hence gestational age and birthweight 8. Recent evidence suggests that some ethnic groups have a higher rate of PTB but also have lower rates of neonatal complications than other ethnic groups at the same gestational age 9. All of these perspectives open up new ways to better understand the timing of spontaneous preterm and post-term birth. In recent years, the survival of extremely preterm infants has improved and the threshold of viability is now at 22–23 weeks of gestation. However, concerns about disability and high costs make intensive care at the limits of viability controversial, and questions have been raised as to whether pro-active perinatal and neonatal care might result in increasing numbers of survivors with severe morbidities. To provide up-to-date information, a national collaborative project (EXPRESS) was initiated in Sweden 10. From 1 April 2004 to 31 March 2007, data were collected prospectively on all 1011 infants born in Sweden before 27 completed weeks of gestation (incidence 3.3/1000). Seventy per cent of the infants were live-born, 54% were males and 22% were delivered from multiple pregnancies. Of 844 babies alive on admission, 8.4% died in utero before labor and 7.8% died intrapartum. Of pregnancies with liveborn extremely preterm infants, 60% of the mothers had received tocolysis, 87% antenatal corticosteroids and 50% were delivered by cesarean section (CS). Survival at 1 year of age was 70% (10% at 22 weeks, 53% at 23 weeks, 67% at 24 weeks, 81% at 25 weeks, and 85% at 26 weeks), which was higher than reported from other population-based studies. Of perinatal interventions, the following were significantly associated with a decreased risk of postnatal death: tocolysis, antenatal steroids, birth at a level III hospital, surfactant administered within 2 h of birth. Cesarean section increased the chances of survival during the first 24 h of life, but not later 11. Among 1-year survivors, 45% (from 17% at 22–23 weeks to 63% at 26 weeks) had no major neonatal morbidity. Despite the overall excellent outcome, there were significant regional differences in survival. The 1-year survival of infants born at 22–24 weeks was higher in the three healthcare regions with more active perinatal care compared with the four regions with lower activity levels, but by 25–26 weeks there were no significant differences in outcome 12. At the age of 2.5 years, 456 extremely preterm infants and 715 matched controls born at term were examined by a pediatrician, a psychologist (Bayley-III test), and an ophthalmologist. In addition, the parents were interviewed about the health status and behavior of the children. In the extremely preterm group, 7% had cerebral palsy, 1% blindness, and 1% moderate or severe hearing impairment. Overall, 42% of extremely preterm infants had no disability, 31% had mild, 16% moderate, and 11% had severe disability 13. Moderate or severe disability decreased with gestational age. Vaginal breech delivery, male gender and Apgar scores <7 at 5 min were significantly associated with mental developmental delay. A corresponding follow-up examination was performed at 6.5 years of age (441 extremely preterm children, 371 controls). At that age, 36% of extremely preterm infants had no disability, 30% had mild, 19% moderate, and 14% had severe disability (unpublished data). In summary, the Swedish EXPRESS study showed that proactive perinatal management led to a high survival of infants born before 27 gestational weeks (70%). The neonatal morbidity was considerable, but not higher than reported from other population-based studies with lower survival. At 1 year of age, 45% of infants had no severe morbidity. Follow up at 2.5 years showed that the neurodevelopmental outcome was poorer than in children born at term, but 73% of extremely preterm infants had no, or only mild disability. The corresponding figure at 6.5 years was 66%. The conclusion was that in this Swedish study improved survival of extremely preterm infants was not associated with increased morbidity. Ingemarsson himself was a trailblazer with respect to proactive perinatal management at the limits of viability 14. Ingemar's PhD thesis in the 1970s was on the pharmacological inhibition of myometrial contractility using the β2-agonist terbutaline and this was the subject of his first published randomized placebo-controlled trial 15. Since that time, tocolytic options for the management of preterm labor have evolved during which time tocolytic myths and legends have led to limitations of use, and at times therapeutic nihilism. One claim is that despite tocolytics, the rate of PTB has not decreased in the last few decades. This is because we now include births of extremely low birthweight infants around the limits of viability, which were not included in statistics 30–40 years ago. In addition, the risk factors for PTB such as drug abuse, medically assisted conception, increased maternal age and elective PTB for materno–fetal indications have increased the rate. Indeed, the recent fall in PTB rates in the USA is attributed to reducing elective CS before 37 completed weeks. Another claim is that tocolytics do not reduce perinatal mortality or morbidity. This may be true, but requires qualification. No tocolytic study has been sufficiently powered with a sufficient sample size to demonstrate such an effect. Accordingly, we must take a leap of faith and use the surrogates of in utero transfer and antepartum glucocorticoids, both of which have been demonstrated to be associated with reduced perinatal mortality and morbidity and are two major indications for tocolytic use. In addition, the use of tocolytics before 34 completed weeks of gestation with intact membranes, and before 32 completed weeks of gestation with ruptured membranes, shows no adverse effects on mortality 16 and in the EXPRESS study outlined above, of perinatal interventions, the use of tocolytics, was among those significantly associated with a decreased risk of postnatal death 10. Lack of proof of effect is not the same as proof of lack of effect. The perfect tocolytic that is 100% safe and effective does not exist and the search continues. Currently, magnesium sulfate, though neuroprotective to infants, is considered ineffective as a tocolytic, and unpleasant for women, such that in the USA there has been a call for a ‘time to quit’. Insufficient information exists to support the use of nitric oxide donors for the treatment of preterm labor and while prostaglandin synthetase inhibitors like indomethacin are effective, adverse effects such as oligohydramnios, premature closure of the fetal ductus arteriosus and sudden fetal deaths have led to the recommendation that they should not be used after 28–30 weeks of gestation. Accordingly, atosiban, nifedipine and β2-agonists currently compete for the position of first-choice tocolytic with pros and cons for safety, efficacy and cost. Nifedipine is cheap and can be given orally, but there are concerns about the quality of studies used to provide guidelines for its use as a tocolytic 17, as well as concerns for safety particularly when used in combination with other tocolytics 18. Unlike nifedipine, β2-agonists are licensed for use as a tocolytic but concerns remain with respect to serious complications such as pulmonary edema 19. Atosiban is much more expensive than other tocolytics, but the evidence base for atosiban is the most robust of all tocolytics. Atosiban is more effective than β2-agonists, and with respect to safety, is 10 times less likely to cause cardiovascular side-effects and 15 times less likely to require discontinuation of therapy because of unacceptable side effects compared with β2-agonists 20. Combined therapy around the limits of viability is a novel concept addressed directly by Ingemarsson who evaluated the use of more than one tocolytic, antibiotics and antepartum glucocorticoids in women with preterm labor at <26 weeks gestation with excellent results 14. Ingemarsson also had a passion for the gender aspects of PTB and readers are encouraged to peruse a fascinating review he produced for the proceedings of the 2nd International Preterm Labour Congress in Montreux in 2002 21. Obesity in pregnancy is a major source of potentially preventable perinatal morbidity. During recent decades there has been a significant increase in the incidence of obesity. There is evidence that obesity may be a risk factor for PTB, but the details of this relation are not completely understood and often inconsistent. Results from new, large, population-based studies from Sweden 22 and California 23 took into account a more complex interaction. In a review including results from both the Swedish and Californian studies, and comprising almost 3.5 million births, the phenotype of PTB was considered 14, 24. Both spontaneous and medically induced deliveries were analyzed as well as the impact of gestational age by dividing births into extremely preterm, very preterm and moderately preterm deliveries as well as considering the dose–response relation to an increasing body mass index. They found that increasing levels of obesity lead to PTB by two mechanisms. Comorbidities associated with obesity such as gestational diabetes and hypertension, increase the PTB rate and PTBs secondary to these comorbidities occur in both spontaneous and medically induced births across all gestational ages. Excluding the women with comorbidities, PTB appears to be due to obesity per se, particularly in very early PTBs. Based on these studies, initiatives and interventions to reduce obesity can constitute important strategic approaches to reduce both spontaneous and medically induced PTB. Lifestyle interventions for obese pregnant women have the potential to restrict excessive gestational weight gain 25. However, interventional studies have not been successful in reducing maternal and neonatal outcomes such as gestational diabetes, preeclampsia and large-for-gestational age infants 26, 27. Complications that may be associated with an unfavorable metabolic milieu in early gestation will not be amenable to interventions used in the second trimester. No lifestyle intervention studies in obese women have been designed with the primary aim to reduce the risk of spontaneous PTB. It is likely that the international collaboration on individual patient data meta-analysis on weight management in pregnancy 28 will be able to shed light on some of these issues. In the meantime, efforts should be employed to optimize pregestational bodyweight and the metabolic conditions before conception. Had the globesity epidemic been evident during Ingemar's academic career, we are confident he would have been active in the fight against the problem because of the related fetomaternal mortality and morbidity and the association with PTB. Ingemarsson had an important interest in the mode of delivery of the preterm infant and was a supervisor of Professor Magnus Westgren whose PhD thesis was on this subject 29, 30. In both term and PTB, vaginal birth (VB) should be the preferred route with respect to the mother, as it is associated with lower morbidity and mortality. The etiology of complications after preterm CS is uncertain, because it is difficult to determine whether it is the CS by itself or the underlying indication for the CS that causes the complication. At early gestations, the lower segment of the uterus is poorly formed or undeveloped. Accordingly, at the time of preterm CS it may be necessary to perform a low classical uterine incision or a T- or J-incision on the uterus. There are higher maternal risks pertaining to a CS compared with VB, such as maternal death (three- to five-fold), hysterectomy (two-fold), intensive care/hospital stay >7 days (two-fold), postnatal infections, thromboembolism, and excessive blood loss. The decision with respect to mode of delivery is influenced by a number of factors (Table 1). Around the limits of viability (22–26 completed weeks of gestation) the decision may be particularly problematic and full discussion with the parents should involve the neonatal pediatricians. There are fetal risks of CS compared with VB. A poorly formed lower uterine segment may cause technical difficulties when delivering the infant leading to intracranial hemorrhage and injury to the limbs, skin and abdominal viscera. One method of delivering the preterm infant by CS to protect against such injuries is using birth “en caul”, where the fetus is delivered within an intact amniotic sac 31. With elective CS without labor there is the additional risk of transient neonatal tachypnea as well as idiopathic respiratory distress syndrome. Furthermore, there is a risk of iatrogenic PTB where a planned CS may be a consequence of misdiagnosed labor. To date, only six randomized controlled trials to determine the optimum mode of delivery for the very preterm infant have been performed and all six trials were stopped early due to small numbers. These trials did not yield enough evidence to evaluate the use of planned CS compared with VB in spontaneous preterm labor. However, there were seven cases of major maternal postpartum complications following CS compared with none following VB 32. In general, VB is preferred for the preterm infant presenting cephalically, but CS can be justified for different fetomaternal indications. For the preterm infant presenting as breech, the risk of fetal complications after VB appears to be higher and hence a CS is often preferred 33. Before 32 completed weeks of gestation and/or with breech presentations with an estimated fetal weight < 1500 g there is a substantial body of retrospective, descriptive literature that supports CS, due to reduced neonatal mortality and morbidity 30. The risks pertaining to VB include a higher incidence of footling breech presentation with greater likelihood of cord accidents and increased risks of asphyxia. Furthermore, there is a higher risk of entrapment of the after-coming head through an incompletely dilated cervix. Infant mortality and morbidity following PTB presenting by the breech is inversely proportional to gestational age and several reviews confirm this 34. Large register studies from the Nordic countries support these findings and report that VB of preterm infants is associated with a small but increased risk of infant death in breech and multiple births. In VB of vertex presentations there was no increased risk (excluding cases with preeclampsia) 33, but the risk of developmental delay at 2.5 years doubled with VB delivery of preterm infants at 22–27 weeks of gestation 10, 11. It is generally accepted that vacuum extraction should not be performed before 34 weeks of gestation because of the higher risk of cephalhematoma and intracranial hemorrhage. The use of forceps or episiotomy does not improve outcome. There are very few studies, most of which are inconclusive, on neonatal outcome after vacuum extraction for PTB. In general, the rate of vacuum extraction in PTB is very low, but is associated with a higher risk of intracranial and extracranial hemorrhage, and brachial plexus injury, which is in contrast to CS during preterm labor compared with VB 35. Ingemar Ingemarsson was loved by patients, colleagues, and trainees alike, and his attributes as a clinician researcher, teacher, mentor, and role model have been rightly lauded 1. In the time available in the symposium, it was not possible to cover comprehensively Ingemar's contribution to fetomaternal care. What we hoped to achieve was to reflect why Ingemar's interest in the subject of PTB was so important and to emphasize that he is sorely missed and will always be thought of as the baby's friend.

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